Diabetes mellitus and its complications are now considered to be the third leading cause of death in Canada and the United States, trailing only cancer and cardiovascular disease.
Treatment with modified fatty acids represent a new way to treat these diseases.
EP 345.038 and PCT/NO95/00195 describes the use of non-xcex2-oxidizable fatty acid analogues.
It has now been found that these have broader area of applications.
Further, we have now synthesized and characterized novel fatty acid analogous which impose an effect on diabetes.
In feeding experiments with the fatty acid the results show that these compounds lower the adipose tissue mass and body weight, and are thus potent drugs for the treatment of obesity and overweight.
Further, we have shown that the fatty acid analogues are potent antidiabetic compounds, with a profound effect on the levels of glucose and insulin.
Further, the compounds have been proved to have an favourable effect on restenosis, and exhibit good anti-oxidative properties.
DIABETES
Diabetes mellitus and its complications are now considered to be the third leading cause of death in Canada and the United States, trailing only cancer and cardiovascular disease. Although the acute and often lethal symptoms of diabetes can be controlled by insulin therapy, the long-term complications reduce life expectancy by as much as one third. Compared with rates of incidence in nondiabetic normal persons, diabetic patients show rates which are increased 25-fold for blindness, 17-fold for kidney disease, 5-fold for gangrene, and 2-fold for heart disease.
There are 2 major forms of diabetes mellitus. One is type I diabetes, which is also known as insulin-dependent diabetes mellitus (IDDM), and the other is type II diabetes, which is also known as noninsulin-dependent diabetes mellitus (NIDDM). Most patients with IDDM have a common pathological picture: the nearly total disappearance of insulin-producing pancreatic beta cells which results in hyperglycemia.
Considerable evidence has been accumulated showing that most IDDM is the consequence of progressive beta-cell destruction during an asymptomatic period often extending over many years. The prediabetic period can be recognized by the detection of circulating islet-cell autoantibodies and insulin autoantibodies.
There is a need for a compound which would be nontoxic and have no side effects but which would prevent clinical IDDM and NIDDM.
Type I diabetes: severe diabetes mellitus, usually of abrupt onset prior to maturity, characterized by low plasma insulin levels, polydipsia, polyuria, increased appetite, weight loss and episodic ketoacidosis; also referred to as IDDM.
Type II diabetes: an often mild form of diabetes mellitus, often of gradual onset, usually in adults, characterized by normal to high absolute plasma insulin levels which are relatively low in relation to plasma glucose levels; also referred to as NIDDM.
Type I and II diabetes are in accordance with an etiologic classification considered as  less than  less than primary greater than  greater than  diabetes respectively.
Secondary diabetes comprises pancreatic, extrapancreatic/endocrine or drug-induced diabetes. Further, some types of diabetes are classified as exceptional forms. These include lipoatrophic, myatonic diabetes, and a type of diabetes caused by disturbance of insulin receptors.
Considering the high prevalence of diabetes in our society and the serious consequences associated therewith as discussed above, any therapeutic drug potentially useful for the treatment and prevention of this disease could have a profound beneficial effect on their health. There is a need in the art for a drug that will reduce the concentration of glucose in the blood of diabetic subjects without significant adverse side effects.
It is therefore an object of the present invention to provide a treatment regimen that is useful in lowering the blood glucose and to treat a diabetic condition.
It is yet another object of the invention to provide a treatment regimen that is useful in lowering the concentration of insulin in the blood, and to increase the effect of the remaining insulin.
MECHANISMS OF ACTION
Minor modifications of natural fatty acids, sulphur, selenium or oxygen replacing one or more of carbons in the fatty acid backbone. The compounds defined by the formula I have properties which give them a unique combination of biological effects.
Tetradecylthioacetic acid (TTA) is most thoroughly studied and we have shown several beneficial effects in various test animals.
The studies have shown that TTA has properties very similar to natural fatty acids, the main difference being that TTA is not oxidised by the mitochondrial xcex2-oxidation system. However, the presence of compounds of the present invention have been shown to increase the xcex2-oxidation of other (non-substituted fatty acids).
Administration of TTA to rats for 12 weeks nearly doubled the hepatic and plasma content of monounsaturated fatty acids (mainly oleic acid), while polyunsaturated fatty acids (mainly linoleic acid and DHA) decreased. Thus the compound of the present invention modifies the composition of the lipids in various tissues. It is also shown that the present compounds modifies the fat content, and it is anticipated that the present compounds also will modify the fat distribution.
Feeding moderate doses of TTA to animals like rats, mice, rabbits and dogs decreased both plasma cholesterol and triacylglycerol levels within days of treatment. We have also shown the same effect for TSA, and compounds of the present invention with Sulphur substituted in positions 5 or 7 have been shown to increase the xcex2-oxidation and it is thus anticipated that also these fatty acid analogous will lower the plasma levels of triglycerides and cholesterol. TTA and TSA are far more potent in this respect than polyunsaturated fatty acids like EPA.
As mentioned above, an important mechanism of action of 3-thia fatty acids is a significant increased mitochondrial fatty acid oxidation reducing the availability of fatty acids for esterification. The synthesis of triacylglycerol and cholesterol is reduced and the secretion of VLDL from the liver is decreased (10). This has the effect of reducing the production of LDL. All these effects seem to be at least partly mediated by peroxisome proliferator activated receptors (PPAR), ubiquitous transcription factors involved in the regulation of lipid metabolism. We have shown that TTA is a potent ligand of PPARxcex1, a transcription factor regulating the catabolism of fatty acids and eicosanoids, and a less potent ligand of PPARxcex3, which is involved in the regulation of adipocyte differentiation.
Obesity is a common feature of non insulin dependent diabetes mellitus (NIDDM) and a risk factor for its development. NIDDM is often linked to hypertension, dyslipidemia, elevated levels of plasma free fatty acids and an increased risk of cardiovascular disease. NIDDM patients are characterised by resistance to insulin action on glucose uptake in peripheral tissues and dysregulated insulin secretion.
We have shown that TTA decrease hyperinsulinemia and markedly improved insulin action on glucose utilisation. TTA did also prevent diet-induced insulin resistance. In contrast to the prior known antidiabetic glitazones TTA did not increase body weight gain.
These effects may at least partly be explained by increased influx of fatty acids and enhanced fatty acid oxidation in the liver. The data thus suggest a role for TTA in both lipid and glucose homeostasis in vivo.
As clearly shown in the experimental section the compounds of the present invention inhibit an increase in the body weight and adipose tissue mass of animals given either a high fat or a high sucrose diet. This make the compounds of the present invention very suitable as pharmaceutical and/or nutritional agents for the treatment of obesity, i.e. the compounds can be used as a slimming agent to provide a body weight or adipose tissue weigh reduction.
Further the compounds of the present invention can be used as an anti-diabetic drug by reducing the concentration of glucose in the blood. We have also shown that the compounds of the present invention reduce the plasma concentration of insulin in hyperinsulineamic animals. For animals which possesses a reduces sensitivity to insulin, the compounds of the present invention have been shown to strengthen the effect of endogenous insulin.
The term  less than  less than metabolic syndrome greater than  greater than  is used to describe a multimetabolic syndrome which is inter alia characterised by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, Type 2 diabetes mellitus, dyslipidemia or hypertension.
As indicated above the compounds of the present invention have been shown to provide a positive effect on all the conditions mentioned above, i.e. by regulating both the glucose and lipid homeostasis, and thus it is anticipated that the compounds of the present invention will be suitable agents for the regulation of the above defined metabolic disease (sometimes called syndrome X).
The present invention discloses that modified fatty a The present invention discloses that modified fatty acid analogous at non-cytotoxic concentrations can be used for the treatment and/or prevention of obesity, hypertension and fatty liver.
The present invention relates to the use of fatty acid analogues of the general formula (I):
CH3xe2x80x94[CH2]mxe2x80x94[xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number which indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug and complex thereof, for the preparation of a pharmaceutical composition for the treatment and/or prevention of diabetes.
In particular, the invention relates to the use of a compound of the general formula I, wherein the diabetes is type I diabetes.
A preferred embodiment of the invention relates to the use of a compound of the general formula I, wherein the diabetes is type II diabetes.
Still further embodiments relates types of diabetes selected from the group comprising secondary diabetes such as pancreatic, extrapancreatic/endocrine or drug-induced diabetes, or exceptional forms of diabetes such as lipoatrophic, myatonic or a diabetes caused by disturbance of insulin receptors.
One embodiment of the invention is the use of a compound of formula I wherein mxe2x89xa713.
A presently preferred embodiment of the invention comprises the formula I, wherein Xi=3 is selected from the group consisting of O, S, SO, SO2 and Se, and wherein Xi=5-25 is CH2.
Tetradecylthioacetic acid (TTA) and Tetradecylselenoacetic acid (TSA), i. e. Xi=3 is Sulphur and Selenium, respectively is presently preferred compounds.
Still a further aspect of the invention relates to the use a compound of the formula I for the preparation of a pharmaceutical composition for the treatment and/or prevention of the multi metabolic syndrome termed  less than  less than metabolic syndrome greater than  greater than  which is inter alia characterised by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, Type 2 diabetes mellitus, dyslipidemia and/or hypertension.
A further aspect of the invention relates to a method for the treatment or prevention of a diabetic condition, said method comprising the step of administering to an animal in need thereof an effective amount of fatty acid analogues of the general formula (I):
CH3xe2x80x94[CH2]mxe2x80x94[xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number which indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug or complex thereof.
In accordance with the method indicated above, preferred embodiments are as follows:
said animal is a human.
said animal is an agricultural animal, such as gallinaceous birds, bovine, ovine, caprine or porcine mammals.
said animal is a domestic or pet animal, such as dog or cat.
The treatment involves administering to a patient in need of such treatment a therapeutically effective concentration which is maintained substantially continuously in the blood of the animal for the duration of the period of its administration.
Further, the invention relates to a pharmaceutical composition for the prevention and/or treatment of a diabetic condition. Preferably, the pharmaceutical composition comprises in admixture with the fatty acid analogues a pharmaceutically acceptable carrier or excipient.
Further the invention relates to methods for treatment and/or prevention of hyperglycaemia, hyperinsulinemia or reduced sensitivity to insulin, said method comprising the step of administering to an animal in need thereof an effective amount of fatty acid analogues of the general formula (I).
The invention also relates to a nutritional composition comprising an amount of fatty acid analogues of the general formula (I): effective to reduce, or to prevent an increase in the concentration of glucose in the blood of a human or non-human animal.
The invention also relates to novel fatty acid analogous of the formula I
CH3xe2x80x94[CH2]mxe2x80x94[xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number which indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug or complex thereof.